Transformative advances in cancer care will require personalized treatments optimized for individual patients. The unique capability of PET/CT imaging to characterize multiple aspects of tumor function with different tracers-and to do so in a single scan-has great promise for guiding personalized oncology treatment decisions in pancreatic cancer patients. Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death in the United States, with a five year survival rate less than 5%. Most patients are diagnosed with advanced disease, and chemotherapy is the primary treatment option. Recent studies have shown that two therapies currently offer the most promise: gemcitabine-plus-Abraxane or FOLFIRINOX (5-fluoruracil + irinotecan + oxaliplatin), both of which nearly triple response rate by RECIST in the metastatic setting as compared to previous gemcitabine-doublets. While gemcitabine-plus-Abraxane is well tolerated and offers improved quality of life, FOLFIRINOX is much more toxic with difficult side effects. The ability to accurately predict which patients will respond to gemcitabine-plus-Abraxane, and to assess tumor response early in the course of treatment, would allow rational selection between these therapeutic options and offer improved care, survival, and quality of life. This project will study the use of multi-tracer PET/CT imaging to predict and assess response to gemcitabine-plus-Abraxane. A specially- designed triple-tracer technique will be used: fluorothymidine (FLT) to probe nucleoside transporter activity and cellular proliferation + fluorodeoxyglucose (FDG) to probe metabolism + radiolabeled water (H2O) to probe tissue perfusion. Here, similarities between FLT and gemcitabine transport offer a special opportunity to predict gemcitabine response. Similarly, perfusion imaging, especially as coupled with metabolism + proliferation measures, has great potential to elucidate mechanisms of stromal depletion from gemcitabine-plus-Abraxane that may result in increased perfusion and drug delivery to malignant cells. This early phase imaging trial will acquire multi-tracer PET/CT images in 22 patients with pancreatic cancer both before and after 1-cycle of gemcitabine-plus-Abraxane. Imaging results will be correlated with tissue sequencing, immunohistochemistry, and patient outcomes to evaluate imaging biomarker potential for predicting and assessing response to gemcitabine-plus-Abraxane. In addition, the imaging data will be used to develop and evaluate a new technique for rapid single-scan imaging of these tracers, overcoming current technological hurdles to performing multi-tracer PET/CT imaging assessments. Successful completion of this project will provide a new imaging technique, assess novel imaging biomarkers for characterization of pancreatic cancer, and provide initial data on the value of these techniques for image- guided personalized selection of therapy for individual patients. These data will permit the design of future focused clinical trial for translating these new approaches to clinical use.